Deaf gerbils hear again with human stem cells

The procedure needs further animal research to assess safety and long-term effectiveness but researchers said on Wednesday the experiment was an important proof of concept, marking a further advance in the growing field of regenerative medicine.

Marcelo Rivolta from Britain's University of Sheffield, who led the research, said the first patients could receive cell therapy for hearing loss in clinical trials in "a few years".

After treating 18 gerbils with complete deafness in one ear, his team reported in the journal Nature that stem cells produced an average 46 percent recovery in hearing function, as measured by electrical signals in the animals' brains.

"If this was a human patient, it would mean going from being so deaf as to be unable to hear a lorry or truck on the street to being able to maintain a conversation," Rivolta told reporters.

"What we have shown here is functional recovery using human stem cells, which is unique."

Gerbils were selected for the test because their hearing range is similar to that of humans, while mice - the usual choice for laboratory tests - hear at higher frequencies.

The animals were deafened using a drug to destroy their auditory nerves before receiving an injection of around 50,000 human embryonic stem cells, which had previously been treated with growth factors to coax them into becoming ear cells.

The response among the gerbils varied, depending on how well the new cells were integrated into the cochlea, the spiral-shaped cavity in the inner ear.

Deafness is caused primarily by loss of sensory hair cells in the ear and auditory nerves. Since these cells are created only in the womb, there is no way to repair them once they have been damaged, resulting in permanent hearing loss.

Cochlear implants offer a partial solution to loss of hair cells but there is no treatment for nerve loss, or auditory neuropathy, which accounts for 10-15 percent of cases of profound deafness.

Rivolta said stem-cell treatment would initially address nerve damage, although it could also be used in a wider range of patients if it was used in combination with implants.

Significant uncertainties remain.

In particular, the ability of embryonic stem cells to morph into any of the other cell types in the body means they can cause tumors - something that was not seen in the 10-week gerbil study but which Rivolta said needed longer study.

Another danger is that transplanted cells may be rejected by the recipient's immune system.

The research on deafness parallels more advanced work on the eye, where stem cells have already been shown to improve vision in small-scale human tests.

Doctors hope one day to use stem cells to treat a wide range of diseases such as Parkinson's, diabetes and cancer. But localized approaches in the eye or ear may be a promising first step, since fewer cells are involved.

Ralph Holme of the charity Action on Hearing Loss, which helped fund the Sheffield research, said the work was "tremendously encouraging" and gave hope of a fix to some types of hearing loss in the future.

"For the millions of people for whom hearing loss is eroding their quality of life, this can't come soon enough," he said.

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A novel treatment using human embryonic stem cells has successfully restored some hearing to previously deaf gerbils, according to a study published this week in the journal Nature.

Hearing loss is generally caused by the interruption of two different types of cells: The loss of hair cells in the ear, which transform vibrations into electrical signals, and loss of the auditory nerve, which transmits the signals detected by the hair cells to the brainstem. While cochlear implants have proven effective in restoring hearing in cases of hair cell damage, no such treatment has existed for the roughly 10% cases in which the auditory nerve itself is damaged.

The new strategy, designed by Marcelo Rivolta and his team at the University of Sheffield, uses techniques the group has recently developed to coax human embryonic stem cells to differentiate into what are called "otic progenitor cells" -- cells that have the possibility to develop further into either hair cells or auditory nerve cells. The progenitor cells are then transplanted into the ears of gerbils with damaged auditory nerves, and allowed to differentiate further. Gerbils were used in the experiment because they hear a similar range of sounds as humans do.

At that point, the researchers held their breath, hoping that the cells would integrate themselves with the existing infrastructure and take their place in the chain of sensory signaling between the hair cells and the brainstem. In nearly all cases, the scientists could clearly see under the microscope that the new cells had targeted the right spots, reconnecting the hair cells to the brainstem.

But the ultimate test is hearing itself. To test this, the researchers used a standard approach called auditory-evoked responses, which are detected in the brainstem and provide a clear verdict of whether or not sound is being successfully transmitted to the brain.

Control animals with their auditory nerves knocked out did not recover during the experiment -- in order for a sound to register an auditory-evoked response in the brainstem, the control animals basically had to be at a rock concert, requiring a 76-decibel sound. But in the treated animals, that number dropped to 50 decibels on average, and in some animals approached the levels of animals whose hearing was never damaged at all. The strength of the effect was akin to suddenly being able to hear someone talking while previously not being able to hear them yell.

The researchers hope that their method will spark a new interest in using stem cells to treat hearing loss in people, though much work needs to be done before that is a real possibility. Hurdles include developing a surgical technique to access the appropriate part of the ear in people, and ensuring that the treatment sticks over long periods of time.

Nevertheless, the scientists are optimistic that the approach can be directly translated to humans with hearing loss, finally allowing people who cannot benefit from a cochlear implant to hear again.

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Stem Cells Help Deaf Gerbils Hear Again
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A cure for a common form of deafness known as auditory neuropathy is a step closer, after researchers from the University of Sheffield in the UK used human embryonic stem cells to repair a similar type of hearing loss in gerbils.

Project leader and stem-cell biologist Marcelo Rivolta and colleagues report their work in the 12 September online issue of Nature.

Many of the 275 million people worldwide with moderate-to-profound hearing loss have it because of a faulty link between the inner ear and the brain.

Using gerbils and human embryonic stem cells, Rivolta and colleagues describe how they repaired an important part of that link: the auditory nerve.

"We have the proof of concept that we can use human embryonic stem cells to repair the damaged ear," Rivolta told Nature News.

As well as proving that stem cells can repair damaged hearing, the researchers hope the breakthrough will lead to new treatments.

"More work needs to be done, but now we know it's possible," said Rivolta.

For their study, he and his colleagues developed a way to turn human embryonic stem cells into ear cells and then transplanted them into deaf gerbils.

Scientists hope that stem cells will one day treat deafness in humans.
The model of hearing loss they treated in the gerbils is similar to auditory neuropathy in humans, where damage to the cochlear nerve (also known as auditory or acoustic nerve) disrupts or prevents sound signals picked up by the cochlea in the inner ear from reaching the brain.

The problem lies mainly with the neurons or nerve cells connecting the brain to the inner-ear hair cells that translate sound into electrical signals.

People with this form of hearing loss are usually born with it, and some cases are known to be caused by faulty genes that have already been identified.

But there is also increasing evidence that auditory neuropathy can be caused by jaundice at birth and other environmental factors such as exposure to noise can also be risk factors.
The Study
Rivolta has spent the last ten years developing a way to differentiate human embryonic stem cells into auditory neurons and hair cells.

For this study, the team treated stem cells with two types of fibroblast growth factor, FGF3 and FGF10. This produced two types of primordial sensory cell: otic epithelial progenitors (OEPs) which are like hair cells, and otic neural progenitors (ONPs) which are like neurons.

They then transplanted only the ONPs into the ears of gerbils treated with ouabain, a chemical that damages auditory nerves, but not hair cells.

Ten weeks later, some of the transplanted cells had grown projections that connected to the brain stem.

The researchers used a method called ABR (auditory brainstem evoked responses) to measure how well the brain detects an electrical signal after sound stimulation.

Four weeks after transplantation, the average overall improvement in hearing (functional recovery) was 46%.

"The responses of the treated animals were substantially better than those untreated, although the range of improvement was broad. Some subjects did very well, while in others recovery was poor," Rivalto told the press.
Step Forward Likely to Prompt Further Studies
Rivolta said he and his team believe the study is a big step forward, because it shows they now have a way to make human cochlear sensory cells for use in new drugs and treatments, and to study the function of genes.

He said more research is now needed, for example, to understand the long term implications of such a treatment and its safety.

"Moreover, while in auditory neuropathy patients that retain their hair cells the sole application of stem cells could be beneficial; those with more comprehensive damage may need a cochlear implant to compensate for the hair cell deficit. In these patients it is possible that stem cells should be administered in combination with a cochlear implant. It is therefore important to explore this interaction," he explained.

Rivolta's group is not the first to differentiate stem cells into auditory nerve cells, but this is the first report of transplanted cells restoring hearing in animals.

Richard Altschuler, a developmental biologist at the Kresge Hearing Research Institute at the University of Michigan in Ann Arbor, is among those who believe the study is a breakthrough that will now prompt further research.

"Research has been stymied by reviewers wanting evidence that stem cells can connect the inner ear to the central nervous system," he told NatureNews.

Dr Ralph Holme, Head of Biomedical Research for the UK charity Action on Hearing Loss (formerly known as the Royal National Institute for Deaf People, RNID), describes the breakthrough as "tremendously encouraging", raising the real hope that one day it will be possible to fix the actual cause of some types of hearing loss.

"For the millions of people for whom hearing loss is eroding their quality of life, this can't come soon enough," says Holme.

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